CN103703367A - Method for providing oncogenesis information and device for providing oncogenesis information - Google Patents
Method for providing oncogenesis information and device for providing oncogenesis information Download PDFInfo
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Abstract
Provided is a method for providing oncogenesis information, which enables the risk of cancer to be detected with good precision in the early stages of cancer. The method for providing oncogenesis information, which provides information pertaining to the oncogenesis of cells, comprises: a data acquisition step in which measurement data, which includes first data pertaining to the size of the cell nucleus and second data pertaining to the size of the cytoplasm, are acquired for each cell contained in a measurement sample that contains cells collected from epithelial tissue; a data extraction step in which measurement data for cells that are to be analyzed, which include at least some of the cells that are more on the basement membrane side than cells that exist in the surface layer of the epithelial tissue, are extracted from among the measurement data for multiple cells in the measurement sample, on the basis of the first data and second data acquired for each cell; and an information output step in which the extracted measurement data is analyzed, and information pertaining to the oncogenesis of cells is outputted.
Description
Technical field
The present invention relates to a kind of analysis of cells and canceration information providing method and the canceration information provider unit of the canceration relevant information of this cell are provided.
Background technology
People have known the canceration relevant information (such as with reference to patent documentation 1 ~ 2) that has the cell that a kind of analytical equipment can automatic analysis person under inspection and this cell is provided.Patent documentation 1 discloses a kind of device, this device allows the mensuration sample stream via flow chamber of containing the cell that picks up from person under inspection, with the flow through mensuration sample of this flow chamber of irradiation, with this, obtain the scattered light signal of each cell, by analyzing the waveform of each scattered light signal, extract characteristic parameter, with this characteristic parameter, from a plurality of cells, pick out cancer cell and heterocyst (atypical cell).
Patent documentation 2 discloses a kind of pathological diagnosis servicing unit, this device is taken the cell of the flow chamber of flowing through, according to obtained view data, infer nucleus and cytoplasmic distribution, and according to inferred nucleus and cytoplasmic distribution area ratio (N/C ratio), infer the distribution at cancer position in pathological tissue specimen.
look-ahead technique document
patent documentation
Patent documentation 1: No. 2006/103920th, International Publication
Patent documentation 2: No. 2004-286666, JP (Japanese Patent Publication).
Summary of the invention
the problem that invention will solve
Such as, in the histodiagnosis of uterine neck, the process that develops into cancer from normal condition has several stages, is followed successively by " normal (Normal) ", " CIN1 ", " CIN2 ", " CIN3 " and " cancer (Cancer) " from normal condition.Wherein, " CIN1 ", " CIN2 " and " CIN3 " stage all belong to the stage that is known as " Cervical Intraepithelial Neoplasia (CIN) ".
" CIN1 " refers to the state of the secondary basal cell of atypia (atypical) (parabasal cell) propagation to 1/3 place on top layer by basalis, this is a kind of state of probably spontaneous regression.Therefore, " CIN1 " stage it has been generally acknowledged that there is no need treatment." CIN2 " refers to the state of the secondary basal cell propagation of atypia (atypical) to 2/3 place on top layer by basalis, " CIN2 " stage is to it is believed that the state that needs treatment." CIN3 " refers to the state that almost has the secondary basal cell propagation of atypia (atypical) between basalis and top layer everywhere, and " CIN3 " stage is judged as and needs treatment by people.To start as early as possible treatment of cancer, be preferably in cancer and develop to the initial stage of cancer stage of " cancer (Cancer) " " CIN2 " ~ " CIN3 " before and detect the possibility that patient suffers from cancer, and preferably can distinguish patient and need in being judged as without the stage before treatment " CIN1 " or in being judged as " CIN2 " the later stage that treat.
No matter, being judged as without treatment " CIN1 " stage or being judged as " CIN2 " stage that needs treatment, all can there is normal cell to mix existence with cancer cell or heterocyst (atypical cell).Therefore, from person under inspection's uterine neck in " CIN1 " stage, gather cell formation determination sample, from person under inspection's uterine neck in " CIN2 " stage, gather cell formation determination sample, measure in sample and all can have again cancer cell or heterocyst (atypical cell) by existing normal cell, only by detecting this approach of heterocyst (atypical cell), be difficult to accurately detect in the initial stage of cancer stage possibility that patient suffers from cancer.
In the analytical equipment of describing at patent documentation 1 and 2, even to analyzing from the mensuration sample of the person under inspection's uterine neck collection of initial stage of cancer stage, preparation, due to cancer cell or heterocyst (atypical cell) very little at the cell number proportion for analyzing, be therefore difficult to accurately detect in the initial stage of cancer stage possibility that patient suffers from cancer.
In view of this, its object is to provide a kind of can accurately detect canceration information providing method and the canceration information provider unit that patient suffers from the possibility of cancer in the initial stage of cancer stage in the present invention.
the means of dealing with problems
(1) canceration information providing method of the present invention is a kind of canceration information providing method that the relevant information of cell carcinogenesis is provided, it is characterized in that comprising the following steps: data acquisition step, that is, just contain the determination data that each cell contained in the mensuration sample of the cell that picks up from epithelial tissue obtains the second data that comprise first data relevant to nucleus size and be correlated with tenuigenin size; Data extraction step,, according to the first data of obtaining with regard to each cell and the second data, the determination data of extraction and analysis object cell from measure the determination data of a plurality of cells sample, wherein analytic target cell refers to and in epithelial tissue, is positioned at basilar memebrane one side but not at least a portion of the cell on top layer; Information output step, is analyzed and exports the relevant information of cell carcinogenesis that is to extracted determination data.
The existence of the cell at the position such as uterine neck and oral cavity is that plural number kind cell is layered arrangement by top layer one side direction basilar memebrane one side respectively.Such as, in cervical epithelial cells, the layer (top layer) that exists successively the layer (basalis) being formed by basal cell, the layer (parabasal layer) being formed by secondary basal cell, the layer (middle level) being formed by middle layer cells and formed by cells of superficial layer by basilar memebrane one side direction top layer one side, near basal cell basilar memebrane is divided into secondary basal cell, secondary basal cell is divided into middle layer cells, and middle layer cells is divided into cells of superficial layer.In cervical epithelial cells, the cell relevant to canceration is basal cell, and in being developed to the process of cancer, basal cell atypical hyperplasia, becomes heterocyst (atypical cell).Heterocyst (atypical cell) obtains multiplication capacity, and is risen and occupied top layer one side by basalis one side.In addition, the basal cell that atypia (atypical) is changed can break up, therefore, and the secondary basal cell, the middle layer cells that in the process of canceration, there will be atypia (atypical) to change.In the initial stage to cancer development, the cell that atypia (atypical) is changed is present in substrate one side more, and seldom, top layer one side mostly is normal cells of superficial layer to top layer one side.This case inventor is conceived to this just and has completed the present invention.
About canceration information providing method of the present invention, in data extraction step, from measure the cell sample, extract the determination data of analytic target cell that may canceration, analytic target cell is wherein arranged in substrate one side but not at least a portion of the cell on top layer.In other words, by the N/R cells exclude that is positioned at top layer of DNA content outside.Then, to having extracted the cell of determination data, analyze the relevant information of output cell carcinogenesis.Therefore, cancerous tumor cell or the cell in Carcinogenesis can be increased in the shared ratio of the cell for analyzing, the detection sensitivity of above-mentioned cancerous tumor cell or the cell in Carcinogenesis can be improved.
(2) according to the canceration information providing method (1) described, can also design as follows: the first data are for representing the numerical value of nucleus size, the second data are for representing the numerical value of tenuigenin size, just measure sample in data extraction step in, each contained cell is calculated the ratio of the first data and the second data, according to the determination data of the ratio extraction and analysis object cell of obtaining.
(3) according to the canceration information providing method (2) described, can also design as follows: the determination data of the cell of the ratio that extraction is obtained in data extraction step more than first threshold is as the determination data of analytic target cell.
(4) according to the canceration information providing method (2) or (3) described, can also design as follows: the ratio that basis is obtained in data extraction step and the determination data of the second data extraction and analysis object cell.
(5) according to the canceration information providing method (4) described, can also design as follows: in data extraction step, extract the determination data of the cell of the second data below Second Threshold as the determination data of analytic target cell.
(6) according to the canceration information providing method (1) described, can also design as follows: data acquisition step comprises signal acquisition step, signal acquisition step refers to the scattered light signal that obtains the scattered light intensity that represents that illumination mensuration sample produces and the step that represents the fluorescence signal of fluorescence intensity; The first data be take the fluorescence signal waveform that obtains in signal acquisition step be basis, about the data of nucleus size, the second data be take the waveform of the scattered light signal that obtains in signal acquisition step be basis, about the data of tenuigenin size.
(7) according to the canceration information providing method (1) described, can also design as follows: in information output step, with regard to the cytometer as analytic target extracting in data extraction step, calculate the value of reflection DNA content, and according to the value calculating, determine the relevant information of cell carcinogenesis.
(8) according to the canceration information providing method (7) described, can also design as follows: in information output step, according to the value of reflection DNA content, using each cell classification extracting as analytic target for showing first group of normal DNA content and showing second group of DNA content that is greater than normal DNA content range, calculate the ratio of the cell number of the cell number of first group and second group, according to the ratio calculating, determine the relevant information of cell carcinogenesis.
(9) according to the canceration information providing method (1) described, can also design as follows: the number of the cell extracting as analytic target and the 3rd threshold value are compared, if the number of this cell is less than the 3rd threshold value, forbid exporting the relevant information of cell carcinogenesis, or affix represents cell number information seldom when output canceration relevant information.
(10) according to the canceration information providing method (1) described, can also design as follows: the method also comprised the dispersion steps of the aggegation cell in dispersion measurement sample before data acquisition step.
(11) according to the canceration information providing method (1) described, can also design as follows: single epithelial number and the 4th threshold value are compared, if this single epithelial number is less than the 4th threshold value, forbid exporting the relevant information of cell carcinogenesis, or affix represents cell number information seldom when output canceration relevant information.
(12) the canceration information providing method according to (1), can also following design: the cell that cell is uterine neck, and the cell that is positioned at top layer is cells of superficial layer.
(13) according to the canceration information providing method (1) described, all right following design: in information output step, whether output needs the relevant information of reinspection as the relevant information of cell carcinogenesis.
(14) canceration information provider unit of the present invention is a kind of canceration information provider unit that the relevant information of cell carcinogenesis is provided, it is characterized in that: this device comprises data acquisition section and control assembly, wherein data acquisition section just contains each cell contained in the mensuration sample of the cell that picks up from epithelial tissue and obtains and comprise about the first data of nucleus size with about the determination data of the second data of tenuigenin size; Control assembly is according to the first data and the second data obtained with regard to each cell, the determination data that in the determination data of a plurality of cells from mensuration sample, the determination data of extraction and analysis object cell analysis are extracted, the relevant information of output cell carcinogenesis, wherein analytic target cell refers to and in epithelial tissue, is positioned at basilar memebrane one side but not at least a portion of the cell on top layer.
(15) the canceration information provider unit according to (14), can also design: this device also has the flow through mensuration sample of this flow chamber the optical information of obtaining the optical information of cell contained in mensuration sample of the flow chamber crossed for mensuration sample stream and irradiation and obtains parts as follows; Data acquisition section is obtained the first data and the second data according to optical information.
(16) according to the canceration information provider unit (15) described, can also design as follows: this device also has the shooting parts to contained cell is taken in the mensuration sample of the flow chamber of flowing through; The first data are to take the nuclear area that parts photograph, and the second data are to take the cytoplasmic area that parts photograph.
the effect of invention
By canceration information providing method of the present invention and device, can accurately detect the possibility that patient suffers from cancer in the initial stage of cancer stage.
Accompanying drawing explanation
Fig. 1 is the stravismus key diagram of the canceration information provider unit of an embodiment of the present invention;
Fig. 2 is the structured flowchart of canceration information provider unit shown in Fig. 1;
Fig. 3 is the block diagram of the personal computer (personal computer) of the data processing equipment in canceration information provider unit shown in pie graph 1;
Fig. 4 is the structured flowchart of the flow cytometer in canceration information provider unit shown in Fig. 1;
Fig. 5 is the process flow diagram of an example of the flow process of explanation canceration information providing method;
Fig. 6 is the key diagram of determination data;
Fig. 7 is the diagram of an example of scatter diagram;
Fig. 8 is the key diagram that is related to of signal waveform and characteristic parameter;
Fig. 9 is the display case diagram of the display unit of data processing equipment;
Figure 10 is the schematic diagram of cervical epithelial cells;
Figure 11 is the various epithelial cell sizes of uterine neck and the graph of a relation of N/C ratio;
Figure 12 is the histogram of the DNA content of the cell of extraction;
Figure 13 connects by cell cycle and DNA content histogram the diagram describing;
Figure 14 is the key diagram of the relation of each stage and DNA content in the cell cycle;
Figure 15 is the display case diagram of the display unit of data processing equipment;
Figure 16 is the display case diagram of the display unit of data processing equipment;
Figure 17 is the diagram with regard to a histogrammic example of all individual cells draftings;
Figure 18 is the diagram with regard to histogrammic other examples of all individual cells draftings;
Figure 19 is a histogrammic example of drawing at step S9;
Figure 20 is histogrammic other examples of drawing at step S9.
Embodiment
Describe with reference to the accompanying drawings the embodiment of canceration information provider unit of the present invention and canceration information providing method in detail.
[one-piece construction of canceration information provider unit] is in canceration information provider unit 1 shown in Fig. 1 and Fig. 2, allow the mensuration sample stream that contains the cell that picks up from patient (person under inspection) through flow chamber, detect, analyze the light (forward scattering light, side direction fluorescence etc.) obtaining from measuring sample while flowing through the mensuration sample of this flow chamber with Ear Mucosa Treated by He Ne Laser Irradiation, judge thus and in cell, whether contain cancerous tumor cell or be in the cell (being also referred to as below " cancerous tumor cell ") in Carcinogenesis, and export its result.Particularly, canceration information provider unit 1 is for by picking up from patient's cervical epithelial cells examination cervical carcinoma.Canceration information provider unit 1 have carry out the determinator 2 of Specimen Determination etc. and therewith determinator 2 connect and analyze and show the data processing equipment 4 of (output) measurement result etc.As shown in Figure 1, canceration information provider unit 1 also comprises for placing the sample placing components 50 of a plurality of test tubes that hold mixed liquor (without diagram), and wherein said mixed liquor is to take preservation liquid that methyl alcohol is Main Ingredients and Appearance and pick up from the mixed liquor of patient's Biosample.
As shown in Figure 2, the determinator 2 of canceration information provider unit 1 has: the optical information that detects the information such as cell and nuclear size thereof from measuring sample is obtained parts-optical detection parts 3, signal processing circuit 5 namely consisting of flow cytometer, the shooting parts 26 of measuring control assembly 16, the driver part 17 that comprises motor, actuator (actuator) and valve (Valve) etc., various sensor 18 and taking cell image.Signal processing circuit 5 has: the output content of the flow cytometer 3 after prime amplifier (without diagram) is amplified amplifies the analog signal processing circuit of processing and filtering processing etc., the output content of analog signal processing circuit is converted to the A/D converter of digital signal and the digital signal processing circuit that digital signal is carried out to certain waveform processing.Measure control assembly 16 and in the signal of processes sensor 18, control the operation of driver part 17, the suction of measuring sample with this moves and measures.When examination cervical carcinoma, measure sample and can use cell (epithelial cell) to picking up from patient's uterine neck to carry out centrifugal, dilution, stirring and PI dyeing etc. to process and the mensuration sample of preparation.Prepared mensuration sample is contained in test tube and is placed into the certain position place in described sample placing component 50, and then is transported to transfer pipet (without the diagram) lower position of determinator 2, then by this transfer pipet, is inhaled and moves, and is supplied to flow chamber together with sheath fluid.With this, at flow chamber, form sample stream.PI dyeing (DNA dyeing) is to carry out with the fluorescent dye liquid propidium iodide (PI) that contains red pigments.PI dyeing is selectively nucleus to be dyeed, and therefore can detect from nuclear red fluorescence.
[measuring the structure of control assembly] measured control assembly 16 and had microprocessor 20, memory unit 21, I/O controller 22, sensor signal processing element 23, driver part control driver 24 and PERCOM peripheral communication controller 25 etc.Memory unit 21 is by ROM(Read Only Memory, ROM (read-only memory)), RAM(Random Access Memory, random access memory) etc. formation, is storing in ROM for controlling the control program of driver part 17 and carrying out the needed data of this control program.Microprocessor 20 can download to control program in RAM or directly from ROM executive control program.
The signal of sensor 18 is sent to microprocessor 20 by sensor signal processing element 23 and I/O controller 22.Microprocessor 20 just can correspondingly be controlled driver 24 by I/O controller 22 and driver part with the signal of sensor 18 by executive control program and control driver part 17.Data and microprocessor 20 after processing by PERCOM peripheral communication controller 25 and data processing equipment 4 microprocessors such as transmission such as external device (ED) such as grade 20 are processed needed data.
[structure of data processing equipment] as shown in Figure 3, data processing equipment 4, by formations such as personal computers (personal computer), mainly consists of main frame 27, display unit 28 and input block 29.Main frame 27 is mainly by CPU(Central Processing Unit, central processing unit) 27a, ROM27b, RAM27c, hard disk 27d, reading device 27e, I/O interface 27f, image output interface 27g form.Each part mentioned above has all been undertaken communicating to connect by bus 27h.
CPU27a carries out and to be stored in the computer program in ROM27b and to download to computer program in RAM27c etc.CPU27a is serving as and is obtaining aftermentioned about the data of nucleus size with about the data acquisition section of data of tenuigenin size etc., is also serving as the control assembly of extracted cell being analyzed and exported canceration relevant information.
ROM27b consists of mask ROM, PROM, EPROM, EEPROM etc., and it is for storing the computer program carried out by CPU27a and needed data thereof etc.RAM27c consists of SRAM or DRAM etc.RAM27c is for reading the computer program that is stored in ROM27b and hard disk 27d.When carrying out these computer programs, RAM27c is also used as the work space of CPU27a.
Needed data when operating system and application program etc. being installed for the various computer programs of CPU27a execution in hard disk 27d and carrying out above-mentioned computer program.Such as, the Windows(registered trademark of MS's production and sales is installed in hard disk 27d) etc. the operating system of graphic user interface is provided.For making aftermentioned Wave data, calculate the computer program that N/C compares etc. and carry out the needed data of this computer program and be arranged on hard disk 27d.
Running program is also installed in hard disk 27d, and this running program transmits and measures instructions (job command), accepts and process the measurement result that determinator 2 records, the analysis result after Graphics Processing etc. for the mensuration control assembly 16 to canceration information provider unit 1.This running program is moved in aforesaid operations system.
Reading device 27e, by formations such as floppy disk, CD-ROM driver or DVD-ROM drivers, can read computer program or the data of in removable storage medium, storing.I/O interface 27f consists of the parallel interfaces such as serial line interfaces such as USB, IEEE1394, RS-232C, SCSI, IDE, IEEE1284 and analog interface of being comprised of D/A converter and A/D converter etc. etc.I/O interface 27f is connecting the input block 29 consisting of keyboard and mouse, and user can be by operation inputting part part 29 to personal computer (personal computer) input data.I/O interface 27f is connected with determinator 2, can transmit data etc. with this determinator 2.
[flow cytometer and the structure of taking parts] Fig. 4 obtains the optical detection parts 3 of parts and the structural drawing of taking parts 26 for forming optical information.Optical detection parts 3 consist of flow cytometer, and optical detection parts 3 have the light source 53 being comprised of semiconductor laser.The laser that light source 53 penetrates is thus gathered in the mensuration sample of the flow chamber 51 of flowing through after lens combination 52.Under this Ear Mucosa Treated by He Ne Laser Irradiation, measuring the forward scattering light that the cell in sample produces is detected by photodiode (light receiving component) 55 through object lens 54 and filtrator 57.Lens combination 52 consists of the lens group that comprises collimation lens, cylindrical lens and collector lens etc.
Side direction fluorescence and side scattered light that cell produces are injected dichronic mirror 61 by being configured in the object lens 56 of flow chamber 51 sides.Side direction fluorescence and the side scattered light of these dichronic mirror 61 reflections are injected dichronic mirror 62.
The side direction fluorescence going out from dichronic mirror 62 transmissions is detected by photomultiplier 59 after filtrator 63.The side scattered light of dichronic mirror 62 reflections is detected by photomultiplier 58 after filtrator 64.
As shown in Figure 2, signal processing circuit 5 through filtering process and the signal processing such as A/D conversion process after the forward scattering light data, side scattered light data and the side direction fluorescence data that obtain by microprocessor 20, by PERCOM peripheral communication controller 25, be sent to described data processing equipment 4 and deposit hard disk 27d in.Data processing equipment 4 calculates tenuigenin and nuclear width and N/C according to forward scattering light data, side scattered light data and side direction fluorescence data to be compared etc.
About light source 53, also can replace semiconductor laser with gas laser, but from the viewpoint of low-cost, miniaturization and low power consumption, to adopt semiconductor laser to be advisable.Adopt semiconductor laser not only can reduce cost of products, miniaturization and power saving that can also implement device.What use in the present embodiment is to be conducive to light to be brought together as blue semiconductor laser narrower light beam, that wavelength is shorter.It is also effective that blue semiconductor laser has been encouraged wavelength to the fluorescence of PI etc.In addition, light source 53 also can be used the red laser diode low-cost in semiconductor laser, the life-span is long and manufacturer-supplied is stable.
In the present embodiment, except flow cytometer 3, be also provided with and take parts 26.This takes parts 26 as shown in Figure 4, has the light source 66 and the CCD camera 65 that pulsed laser, consist of.The laser that pulsed laser 66 sends is injected flow chamber 51 after lens combination 60, then by object lens 56 and dichronic mirror 61, and in camera 65 imagings.Pulsed laser 66 is can be at certain hour luminous and camera 65 can be taken.
As shown in Figure 2, the cell image that camera 65 photographs is transported to data processing equipment 4 by microprocessor 20 by PERCOM peripheral communication controller 25.The image of cell deposits accordingly hard disk 27d in described forward scattering light data, side scattered light data and the side direction fluorescence data of this cell in data processing equipment 4.
[canceration information providing method], below with reference to Fig. 5, illustrates an example of the flow process of the canceration information providing method of using by canceration information provider unit 1 in present embodiment.
While analyzing with canceration information provider unit 1, first by user, to picking up from the cell (epithelial cell) of patient's uterine neck, remove aggegation cell, PI dyeing and other pre-treatment, formation determination sample.Then, the test tube of the preservation liquid that to be equipped with through the mensuration sample of pre-treatment and the methyl alcohol of take be principal ingredient is placed into sample placing component 50 by user, starts to analyze with canceration information provider unit 1.
Although the DNA content of individual cells is normal, a plurality of cell agglutinations get up to cause to measure DNA content and are shown as exceptional value, can cause thus analysis precision to decline, and remove aggegation cell just in order to prevent this situation.The operation of this removal aggegation cell can realize by processing that scatter operation and filter operation are combined and to the processing that Biosample applies ultrasonic vibration, wherein said scatter operation is to disperse the cell in this Biosample with the rotating shaft that motor rotation is configured in the Biosample after dilution, and described filter operation is to allow the Biosample after disperseing also remove thus aggegation cell by filtrator.Process (ultrasonic vibration processing) about rear one, ultrasonic vibration causes cavitation (cavitation, the generation of minute bubbles and bubble break) in Biosample, and the impact now followed (pressure variation) can disperse aggegation cell.
The microprocessor 20 of the determinator 2 of the canceration information provider unit 1 that Fig. 5 is present embodiment is implemented with the CPU27a of data processing equipment 4, the CPU27a from user to data processing equipment 4 assigns to measure and starts to start till the process flow diagram of the processing of canceration information is provided indication.Connecting the power supply of data processing equipment 4 and the computer program being stored in this data processing equipment 4 has been carried out after the operations such as initialization, user just assigns to measure and starts indication.User assigns to measure to CPU27a and starts after indication, and CPU27a starts by mensuration the microprocessor 20 that indication is sent to determinator 2.Then, receive mensuration start after indication at microprocessor 20, in determinator 2, transfer pipet is inhaled to move and is contained in invisible spectro mensuration sample, and is supplied to flow chamber shown in Fig. 4 51, forms sample stream (step S1).
Then, the Ear Mucosa Treated by He Ne Laser Irradiation cell in the mensuration sample of flow chamber 51 of flowing through, is detected by photodiode 55 from the forward scattering light of this cell, and side scattered light is detected by photomultiplier 58, and side direction fluorescence is detected by photomultiplier 59.
Then, forward-scattering signal, lateral scattering light signal and the side direction fluorescence signal of flow cytometer 3 outputs are transported to signal processing circuit 5, at signal processing circuit 5, through certain, process, obtain thus the forward scattering light data of reflection forward scattering light intensity, side direction fluorescence data and the aftermentioned characteristic parameter (step S2) of the side scattered light data of reflection lateral scattering light intensity, reflection side direction fluorescence intensity.
Fig. 6 is the key diagram at the determination data of step S2 acquisition.Fig. 6 has shown containing the schematic diagram of nucleolate cell and the waveform of forward-scattering signal and the waveform of side direction fluorescence signal that obtain from this cell.In Fig. 6, the ordinate of chart represents various light intensities.The width means of the waveform of forward scattering light intensity be the numerical value (second data relevant to tenuigenin size) of reflection tenuigenin width, the width means of the waveform of side direction fluorescence intensity be the numerical value (to big or small the first relevant data of nucleus) of reflection nucleus width.In Fig. 6 that side direction fluorescence intensity waveform and certain baseline surround, the cartographic represenation of area of shadow region is the DNA content of cell.The first data that calculate each cell at CPU27a and the second data than N/C ratio, calculate the ratio ratio of the width of forward-scattering signal waveform (width of=side direction fluorescence signal waveform with) of nucleus size and cell size.
After step S2, microprocessor 20 is sent to data processing equipment 4(step S3 at interior determination data by PERCOM peripheral communication controller 25 by being included in forward scattering light data, side scattered light data, side direction fluorescence data and the characteristic parameter that step S2 obtains), end process then.
Then, CPU27a judges whether to have received determination data (step S4) from microprocessor 20.At step S4, if CPU27a judgement is not received determination data (step S4 is no) from microprocessor 20, repeatedly carry out the processing of step S4 until receive determination data.On the other hand, at step S4, if CPU27a judgement has been received determination data (step S4 is yes) from microprocessor 20, processing is advanced to step S5.
At step S5, CPU27a draws scatter diagram as shown in Figure 7.The scatter diagram of drawing can be presented on the display unit 28 of data processing equipment 4.The ordinate of this scatter diagram is cell size, and horizontal ordinate is described N/C ratio.When picking up from normal person's cervical epithelial cells with 1 analysis of canceration information provider unit, the scatter diagram of drawing at step S5 as shown in Figure 7, is the sagging crescent distribution in the right.
At step S5, draw out after scatter diagram, at step S6, CPU27a judgement has obtained in the cell of determination data whether have 5000 (the 4th threshold values) above single epithelial cell.In the present embodiment, this judgement is carried out with following methods described in patent documentation 1.
That is, can use following numerical value: from the waveform signal of forward direction scattered light, obtain with difference product score value divided by the resulting Characteristic parameter B of peak value or standardization (normalized) second moment, i.e. characteristic parameter M.For example take 20nsec as the sample period X0, X1, X2 ... Xn is by without illustrated A/D converter, waveform signal being sampled, with 8 bits (bit) resolution electronization, convert the measuring voltage between maximum voltage 10V and baseline (Base Line) voltage 0.05V to digital signal.
Following formula for Characteristic parameter B (1) represents.
[several 1]
At this, so-called difference product divides the accumulative total additive value of absolute value of the difference of the sampled data that value representation is adjacent, Peak, i.e. and peak value, refers to and the maximal value (with reference to Fig. 8) of waveform represents in order to following formula (2).
[several 2]
Characteristic parameter M is by representing with following formula (3).
[several 3]
Wherein, P is the subscript letter of Xp while being peak value, Width, i.e. and width, refers to and is greater than as shown in Figure 8 baseline---is the width of the part of Base Line, in order to following formula (4), represents.
[several 4]
Wherein, P is the subscript letter of Xp while being peak value.For judging that whether cell is that the threshold value of individual cells is to wait for parameters and set by experiment.In the present embodiment, use characteristic B parameter for example, the cell that this Characteristic parameter B is reached more than 2.2 is judged as aggegation cell, less than 2.2 be judged as individual cells.The in the situation that of use characteristic parameter M, this characteristic parameter M can be decided to be to aggegation cell at more than 2100 cells, the individual cells that is decided to be less than 2100.
Described " 5000 " these numerals (threshold value) are numerals of generally using as the whether appropriate index of judgement cyto-diagnosis inspection.Also this numeral " 5000 " is used as to the threshold value that guarantees analysis precision in the present embodiment.
At step S6, when 5000 of the number deficiency of judgement individual cells, CPU27a does not carry out the analytic target cell extraction operation of aftermentioned step S7, directly enters step S13.At step S13, the information that CPU27a cannot judge the mensuration sample of preparing in step S1 is presented at display unit 28(step S13 as illustrated in fig. 9).
At step S6, when the number of judgement individual cells is when more than 5000, CPU27a use cell size and N/C are than the determination data (step S7) of these two parameter extraction analytic target cells.
[extraction of the determination data of analytic target cell (step S7)] done in the uterine neck of main analytic target and the epithelial tissue of oral mucosa by canceration information providing method of the present invention and device employing, and plural number is planted cell and from basilar memebrane, started to be successively stratiform existence respectively.In this manual, take the side that basilar memebrane is positioned at upper strata during as lower floor is called as top layer.In uterine neck and oral mucosa, a side adjacent with the external world is equivalent to top layer one side.
As shown in figure 10, at uterine neck place, by basilar memebrane one side, played the layer (top layer) that has formed successively the layer (basalis) being formed by basal cell, the layer (parabasal layer) being formed by secondary basal cell, the layer (middle level) being formed by middle layer cells and formed by cells of superficial layer.Near basal cell basilar memebrane is divided into secondary basal cell, and secondary basal cell is divided into middle layer cells, and middle layer cells is divided into cells of superficial layer.At oral mucosa place, by basilar memebrane one side, rise and be formed with successively basal cell layer, stratum spinosum epidermidis, granular cell layer and cuticula.Following table 1 is shown in the conclusion of above content.
[table 1]
As mentioned above, in the plural number kind cell of epithelial tissue, the cell relevant to canceration is basal cell in cervical epithelial tissue, is basal cell in oral mucous epithelia tissue.In being developed to the process of cancer, basal cell atypia (atypical) propagation, becomes heterocyst (atypical cell).Heterocyst (atypical cell) obtains multiplication capacity, by basalis one side, is risen and is started to occupy top layer one side.For this reason, in the initial stage to cancer development, in the cell in the basalis in cervical epithelial tissue, parabasal layer and middle level, have a large amount of cancerous tumor cells, and there are a large amount of cancerous tumor cells in the cell that is arranged in basal cell layer and stratum spinosum epidermidis in the epithelial tissue of oral mucosa.On the contrary, in the initial stage to cancer development, the cell in the layer of top layer one side of the epithelial tissues such as cuticula of the top layer of cervical epithelial tissue and oral mucous epithelia tissue is cancerous tumor cell rarely.
Known in above-mentioned epithelial tissue, by the layer of basad film one side of layer of top layer one side, cell size diminishes gradually, but that nuclear size becomes is gradually large.Therefore the N/C that, represents nucleus size and the ratio of cell size is than also becoming gradually large by the layer of basad film one side of layer of top layer one side.Therefore, in the present embodiment, with cell size with N/C than the determination data of extraction and analysis object cell.Particularly, at step S7, extract cell size more than 10 μ m below 50 μ m, N/C is than the determination data at more than 0.2 cell below 1.
Judge the criterion whether cell should extract as analytic target, cell size (Second Threshold) and N/C can organize to set by observation and analysis sample according to the kind of serving as the epithelial tissue of analytic target than (first threshold).Such as, take in the cervical carcinoma screening that cervical epithelial tissue is analytic target, can using N/C than more than 0.2 and cell width (cell size) below 50 μ m as criterion.The form that forms each cell of cervical epithelial tissue is summarized in following table 2 with size and nuclear size.Take horizontal ordinate as N/C ratio, in the coordinate that the ordinate of take is cell size, mark and draw each cell, acquired results as shown in figure 11.
[table 2]
From Figure 11 and table 2, learn, for cervical epithelial tissue, extract N/C than more than 0.2 and the cell of cell width below 50 μ m, just can substantially the cells of superficial layer in the few top layer of cancerous tumor cell be got rid of outside analytic target thus, the cancerous tumor cell of only take is obviously analytic target more than middle layer cells, secondary basal cell and basal cell in the layer on top layer.In Figure 11, for the ease of understanding, cells of superficial layer proportion in total cellular score is very little, but the cells of superficial layer number in fact picking up from person under inspection's cervical epithelial tissue is more than other cells.Therefore,, if using all cells that gathers as analytic target, even contain cancerous tumor cell in this cell, its existences also can be diluted, and therefore can not be judged as and need reinspection (positive).That is,, if take all cells gathering is analytic target, be difficult to improve detection sensitivity.
And in fact the cells of superficial layer in the few top layer of cancerous tumor cell is got rid of outside analytic target from the cell gathering, cancerous tumor cell proportion in all cells can be increased, thereby the detection sensitivity of this cancerous tumor cell can be improved.
About canceration information providing method of the present invention, in the cell extraction step of the determination data for extraction and analysis object cell, extract comprise in a way comparatively near the cell in the layer of basilar memebrane, N/C is than larger to a certain extent cell.Cell size and N/C differ than the dispersion having more or less, therefore, in said extracted method, the way of only all cellss of superficial layer being got rid of outside analytic target is impossible in reality, and some cells of superficial layer can be used as analytic target and extract.On the contrary, also can some middle layer cells, secondary basal cell and basal cell be excluded outside analytic target.But, by suitably selecting and serve as cell size and the N/C ratio that extracts criterion, just the extremely low cells of superficial layer of nearly all canceration possibility can be got rid of outside analytic target.
In the present invention, such as extracting basal cell, secondary basal cell and middle layer cells the cell mass forming from basal cell, secondary basal cell, middle layer cells and cells of superficial layer at uterine neck place.The cell mass forming from basal cell, prickle cell, granular cell and cutin at oral mucosa place, extract basal cell and prickle cell.
Return to the process flow diagram of Fig. 5, at step S7, CPU27a extracts N/C than more than 0.2 and the determination data of the cell of cell width below 50 μ m.At following step S8, CPU27a judge N/C than more than 0.2 and the number of the cell of cell width below 50 μ m whether more than 1000 (the 3rd threshold value).If CPU27a judgement N/C than more than 0.2 and the number of the cell of cell width below 50 μ m more than 1000 (step S8 is yes), processing is advanced to step S9, at this step S9 drafting aftermentioned histogram (DNA content histogram).On the other hand, at step S8, if CPU27a judgement N/C is than more than 0.2 and 1000 of the cell number less than of cell width below 50 μ m (step S8 is no), do not carry out the operation of aftermentioned step S11 and step S12, enter step S13.At step S13, the information (step S13) that the mensuration sample that CPU27a is prepared as illustrated in fig. 9 in display unit 28 shows to represent step S1 cannot judge.1000 these numerical value (the 3rd threshold value) be on the basis of considering analysis precision and reliability through various experiments with verify selected numerical value, it is not particularly limited in the present invention.
Figure 12 is a histogrammic example of drawing at step S9.Figure 12 be for the N/C that extracts in step S7 than more than 0.2 and the figure of the cell drafting of cell width below 50 μ m, ordinate represents cell number, horizontal ordinate represents the DNA content of cell.The scope (below also referred to as 2C) that represents normal DNA content is to calculate by the data of a lot of negative sample.In the present embodiment, the scope that represents normal DNA content is set as below the above b of a.The scope that the scope of abnormal DNA content (below also referred to as S more than the phase) is set as being greater than to normal DNA content, is set as being greater than b and the scope below c.The scope of the scope of normal DNA content and abnormal DNA content is not particularly limited in the present invention, and its numerical value is selected by various experiments and checking etc. on the basis of considering analysis precision and reliability.
As shown in figure 13, cell can split into two cells through phenomenons such as DNA replication dnas, chromosome distribution, nucleus division, cytokinesis according to some cycles (cell cycle), then return to origin again.Cell cycle can be divided into the following fourth phase according to its stage, adds the stand-down (G0 phase) that cell proliferation is stopped outside this fourth phase, and cell is always in five certain interim one-phase.The G1 phase: enter preparation and inspection phase before the S phase, the S phase: DNA synthesis phase, G2 phase: preparation and inspection phase before entering the M phase, M phase: division stage.
When cell was bred according to the cell cycle, intracellular nuclear chromosome also can increase, and therefore, measures the DNA content of cell and just can infer which state of this cell in the cell cycle.As shown in figure 14, the DNA content in the G1 phase is certain to normal cell, and in the ensuing S phase, DNA content increases gradually, and the G2 after date entering thereafter just becomes certain value, and this value continued to keep in the M phase.With regard to normal cell, draw DNA content histogram, can obtain histogram shown in Figure 13.The massif correspondence with top the cell of minimum G0 phase of DNA content or G1 phase, and the massif correspondence with the second peak G2 phase or the M phase cell that DNA content is maximum, corresponding the cell of S phase in the middle of it.
In Normocellular situation, the cell number in the interim a certain state of S phase, G2 phase or M is the numerical value in certain limit with the ratio basic display of the cell number in G0 phase or G1 phase.Yet in the time of when cell carcinogenesis or in Carcinogenesis, the numerical abnormalities of chromosomes of this cell increases, therefore, DNA content also increases.Cancerous tumor cell is stronger than normal cell multiplication capacity, therefore the many cell numbers of DNA content increase.
Therefore, the cell number of normal G0 phase or G1 phase of take is benchmark, and the criterion that is compared to by DNA content more than the cell number of this normal cell DNA content and normal cell number, just can infer whether analytic target cell is cancerous tumor cell.Particularly, in the histogram of DNA content shown in Figure 12, the massif correspondence of the leftmost side G0 phase that DNA content is few or the normal cell of G1 phase, and three massif correspondences on its right side DNA content more than the cell of G0 phase or G1 phase normal cell DNA content.Three massifs on above-mentioned right side are considered to be equivalent to the cell (two middle massifs) of the phase of S shown in Figure 13 or the cell (rightmost side massif) of G2/M phase, but if analytic target cell contains cancerous tumor cell, this cancerous tumor cell is also contained in above-mentioned two massifs.And more above-mentioned the number of cancerous tumor cell three massifs are just larger.In Figure 12, for the ease of understanding exemplified with three massifs, but while in fact making DNA content histogram for the cervical epithelial tissue of picking up from person under inspection, can form the state that massif depends on person under inspection.
Therefore, with a plurality of clinical samples that comprise positive sample and negative sample, test and verify, just can select the ratio as criterion thus.In the present embodiment, from obtaining the viewpoint of more than 90% sensitivity, whether criterion is DNA content more than the number of the cell of normal G0 phase or G1 phase cell (cell in normal DNA content range) (cell within the scope of abnormal DNA content) with the ratio of this Normocellular number in 16%(the 5th threshold value) more than.That is, judgement sample being needed recheck (positive) does not still need the critical value of rechecking (feminine gender) to be made as 16%.16% this critical value is not particularly limited in the present invention, can after considering the sensitivity of clinical examination and the balance of specificity, suitably set.
At step S10, if judgement DNA content more than the number of cell (second group) of the cell in normal DNA content range (first group) and the ratio of this normal cell number more than 16% (being yes at step S10), the mensuration sample using in step S11 discriminatory analysis needs to recheck (positive), its result as shown in figure 15, is presented on the display unit 28 of data processing equipment 4.On the other hand, if judge that at step S10 it is no at step S10 that above-mentioned ratio does not reach 16%(), the mensuration sample using at step S12 discriminatory analysis is without rechecking (feminine gender), and its result is presented on the display unit 28 of data processing equipment 4 as shown in figure 16.
The operation (step S7) of the determination data of extraction and analysis object cell and the operation of step S8 in a kind of canceration information provider unit 1 that does not carry out an embodiment of the present invention, but directly with regard to whole single epithelial cells, draw in the histogrammic device of DNA content, to picking up from CIN3(histodiagnosis, being judged as the state of canceration initial stage) cell of person under inspection's cervical epithelial tissue draws out histogram shown in Figure 17 after analyzing.
The operation (step S7) of the determination data of extraction and analysis object cell and the operation of step S8 in a kind of canceration information provider unit 1 that does not carry out an embodiment of the present invention, but directly with regard to whole single epithelial cells, draw in the histogrammic device of DNA content, to picking up from NILM(cyto-diagnosis, being normal state) cell of person under inspection's cervical epithelial tissue obtains histogram as shown in figure 18 after analyzing.
In the canceration information provider unit 1 of an embodiment of the present invention, to picking up from CIN3(histodiagnosis, being judged as the state of canceration initial stage) cell of person under inspection's cervical epithelial tissue is when analyze, and at step S9, draws out the histogram shown in Figure 19.In the canceration information provider unit 1 of an embodiment of the present invention, analyze and to pick up from NILM(cyto-diagnosis and be judged as normal state) during the cell of person under inspection's cervical epithelial tissue, at step S9, draw out histogram shown in Figure 20.
According to the histogram calculation of Figure 17, going out DNA content more than the cell number of DNA content (S is more than the phase) and the ratio of this normal cell number of the cell in normal DNA content range (2C), is 3.2%.According to the histogram calculation of Figure 18, going out DNA content more than the cell number of DNA content (S is more than the phase) and the ratio of this Normocellular number of the cell in normal DNA content range (2C), is 1.1%.Learn thus, do not carry out the determination data extraction operation (step S7) of analytic target cell and the operation of step S8, directly for all single epithelial cells, draw DNA content histogram, in CIN3 person under inspection and NILM person under inspection, DNA content is difficult to occur large gap more than the cell number of DNA content (S is more than the phase) and the ratio of this Normocellular number of normal DNA content range (2C) inner cell.
By contrast, according to the histogram of Figure 19, calculating DNA content more than the cell number of DNA content (S is more than the phase) and the ratio of this Normocellular number of the cell in normal DNA content range (2C), is 57.9%.According to the histogram of Figure 20, calculate DNA content more than the cell number of DNA content (S is more than the phase) and the ratio of this Normocellular number of the cell in normal DNA content range (2C), be 7.4%.Learn thus, the determination data extraction operation (step S7) and the step S8 that carry out analytic target cell draw the histogrammic words of DNA content afterwards again, in CIN3 person under inspection and NILM person under inspection, DNA content is easy to occur large gap more than the cell number of DNA content (S is more than the phase) and the ratio of this Normocellular number of the cell in normal DNA content range (2C).As described herein judgement sample being needed to recheck (positive) does not still need the critical value of rechecking (feminine gender) to be made as 16% words, the person under inspection of CIN3 is judged as needs to recheck (positive), the person under inspection of NILM is judged as not to be needed to recheck (feminine gender), consistent with histodiagnosis or cytodiagnostic judged result.
[other variation] this time disclosed embodiment is illustration in all respects, absolutely not restricted.Scope of the present invention is not limit by the explanation of above-mentioned embodiment, only by shown in the scope of claim, and comprise with claim have same meaning or equal scope in all distortion of holding.
Such as, in the above-described embodiment, obtain the waveform width of forward scattering light intensity as the data of reflection cell size, but also can adopt the peak value of waveform of forward scattering light intensity or the area in the waveform of forward scattering light intensity and the region that necessarily baseline delimited.In the above-described embodiment, the waveform width that obtains side direction fluorescence intensity is as the data of reflection nucleus size, but also can adopt the area in the region that the waveform peak of side direction fluorescence intensity or the waveform of side direction fluorescence intensity and certain baseline delimit.
In the above-described embodiment, if step S6 is judged as NO, the information that output cannot judge, does not carry out the processing of step S11 and step S12, but the invention is not restricted to this.The present invention also can arrange as follows: even if step S6 is judged as NO, also carry out the later processing of step S7, in the judged result that step S11 or step S12 export, affix represents cell number information seldom, then exports in the same old way.In the above-described embodiment, if step S8 is judged as NO, the information that output cannot judge, does not carry out the processing of step S11 and step S12, but the invention is not restricted to this.The present invention also can arrange as follows: even if step S8 is judged as NO, also carry out the later processing of step S9, in the judged result that step S11 or step S12 export, affix represents cell number information seldom, then exports in the same old way.
In the above-described embodiment, the optical information that utilization obtains from flow cytometer is obtained the data that are equivalent to nucleus width cell DNA content, tenuigenin width, but the cell image that also can take parts shooting by analysiss obtains the data that are equivalent to nucleus width cell DNA content, tenuigenin width.
In the above-described embodiment, with histogram shown in Figure 12, the criterion that is compared to DNA content more than the cell number of the DNA content of normal G0 phase or G1 phase cell and this Normocellular number, analyze the cell extracting, but also can analyze without histogram, replace, with scatter diagram shown in Fig. 7, carry out cell analysis.Particularly, also can arrange as follows: in the region (removing delta-shaped region region in addition in above-mentioned quadrilateral) occurring according to region (region for delimiting with triangle in quadrilateral in Fig. 7) and the cancerous tumor cell of the middle layer cells of scatter diagram shown in Fig. 7, secondary basal cell and basal cell appearance, sample is measured in the ratio judgement of included cell needs to recheck (positive) or do not need to recheck (feminine gender).Region in above-mentioned quadrilateral is the region that utilizes cell that each parameter of cell size and N/C ratio is extracted to occur, at the intersection point R of above-mentioned delta-shaped region intermediate cam shape hypotenuse and horizontal ordinate, can set as follows: use comprises that a plurality of clinical samples of positive sample and negative sample are tested and verified and sets.The region of removing in above-mentioned quadrilateral beyond delta-shaped region is the region that the abnormal many cells of DNA content occur, if the ratio of cell that belongs to this region is more than certain value, can judge that this mensurations sample needs reinspection (positive).
In the above-described embodiment, adopt nucleus width/tenuigenin width as N/C ratio, but also can adopt nuclear area/tenuigenin area as N/C ratio.
In the above-described embodiment, in the extraction step of extraction and analysis object cell, extract middle layer cells, secondary basal cell and basal cell, but the invention is not restricted to this, as long as contain some than the cell of more close substrate one side of cells of superficial layer.Specifically, such as extracting secondary basal cell and basal cell, also can extract middle layer cells and secondary basal cell, can only extract middle layer cells, also can only extract secondary basal cell, can also only extract basal cell.In the cell extracting, except the cells such as middle layer cells, also can contain some cells of superficial layer.
In the above-described embodiment, using N/C than with tenuigenin width as the parameter for extracting, but also can only N/C be compared to the parameter for extracting.Now, although the detection sensitivity of cancerous tumor cell slightly declines, due to from having removed tenuigenin width for the parameter of extracting, therefore can improve analysis speed.As shown in Figure 7, the N/C ratio of take is horizontal ordinate, take tenuigenin width as ordinate, the cell of measuring in sample is the sagging crescent distribution in right side, therefore the selected N/C ratio as critical value suitably, just can extract and using that N/C compares and the cell of the almost identical number of cell number that tenuigenin width is extracted during as parameter.
In the above-described embodiment, using the epithelial cell of uterine neck as analytic target, also can using the cell at other positions such as oral cavity as analytic target.
symbol description
1, canceration information provider unit 2, determinator 3, flow cytometer (optical detection parts) 4, data processing equipment 5, signal processing circuit 16, mensuration control assembly 17, driver part 18, sensor 20, microprocessor 25, PERCOM peripheral communication controller 26, shooting parts 27, main frame 27a, CPU 28, display unit 29, input block 51, flow chamber
Claims (16)
1. the canceration information providing method that the relevant information of cell carcinogenesis is provided, is characterized in that, comprising:
Data acquisition step, just contains the determination data that each cell contained in the mensuration sample of the cell that picks up from epithelial tissue obtains the second data that comprise first data relevant to nucleus size and be correlated with tenuigenin size;
Data extraction step, according to the first data of obtaining with regard to each cell and the second data, the determination data of extraction and analysis object cell from measure the determination data of a plurality of cells sample, wherein analytic target cell refers to and in epithelial tissue, is positioned at basilar memebrane one side but not at least a portion of the cell on top layer;
Information is exported step, extracted determination data is analyzed and exported the relevant information of cell carcinogenesis.
2. canceration information providing method according to claim 1, is characterized in that:
The first data are for representing the numerical value of nucleus size, the second data are for representing the numerical value of tenuigenin size, just measure sample in data extraction step in, each contained cytometer is calculated the ratio of the first data and the second data, according to the determination data of the ratio extraction and analysis object cell of obtaining.
3. canceration information providing method according to claim 2, is characterized in that:
The determination data of the cell of the ratio that extraction is obtained in data extraction step more than first threshold is as the determination data of analytic target cell.
4. according to the canceration information providing method described in claim 2 or 3, it is characterized in that:
The ratio that basis is obtained in data extraction step and the determination data of the second data extraction and analysis object cell.
5. canceration information providing method according to claim 4, is characterized in that:
In data extraction step, extract the determination data of the cell of the second data below Second Threshold as the determination data of analytic target cell.
6. canceration information providing method according to claim 1, is characterized in that:
Data acquisition step comprises signal acquisition step, this signal acquisition step refers to obtains the scattered light signal that represents scattered light intensity and the step that represents the fluorescence signal of fluorescence intensity, and described scattered light signal and described fluorescence signal are by illumination, to measure sample to produce; The first data be take the fluorescence signal waveform that obtains in signal acquisition step be basis, about the data of nucleus size, the second data be take the waveform of the scattered light signal that obtains in signal acquisition step be basis, about the data of tenuigenin size.
7. canceration information providing method according to claim 1, is characterized in that:
In information output step, with regard to the cytometer as analytic target extracting in data extraction step, calculate the value of reflection DNA content, and according to the value calculating, determine the relevant information of cell carcinogenesis.
8. canceration information providing method according to claim 7, is characterized in that:
In information output step, according to the value of reflection DNA content, using each cell classification extracting as analytic target for showing first group of normal DNA content and showing second group of DNA content that is greater than normal DNA content range, calculate the ratio of the cell number of the cell number of first group and second group, according to the ratio calculating, determine the relevant information of cell carcinogenesis.
9. canceration information providing method according to claim 1, is characterized in that:
The number of the cell extracting as analytic target and the 3rd threshold value are compared, if the number of this cell is less than the 3rd threshold value, forbid exporting the relevant information of cell carcinogenesis, or affix represents cell number information seldom when output canceration relevant information.
10. canceration information providing method according to claim 1, is characterized in that:
The method also comprised the dispersion steps of the aggegation cell in dispersion measurement sample before data acquisition step.
11. canceration information providing method according to claim 1, is characterized in that:
Single epithelial number and the 4th threshold value are compared, if this single epithelial number is less than the 4th threshold value, forbid exporting the relevant information of cell carcinogenesis, or affix represents cell number information seldom when output canceration relevant information.
12. canceration information providing method according to claim 1, is characterized in that:
Cell is the cell of uterine neck, and the cell that is positioned at top layer is cells of superficial layer.
13. canceration information providing method according to claim 1, is characterized in that:
In information output step, whether output needs the relevant information of reinspection as the relevant information of cell carcinogenesis.
14. 1 kinds of canceration information provider units that cell carcinogenesis relevant information is provided, is characterized in that, comprising:
Data acquisition section, just contains each cell contained in the mensuration sample of the cell that picks up from epithelial tissue and obtains and comprise about the first data of nucleus size with about the determination data of the second data of tenuigenin size;
Control assembly, according to the first data of obtaining with regard to each cell and the second data, the determination data that in the determination data of a plurality of cells from mensuration sample, the determination data of extraction and analysis object cell analysis are extracted, the relevant information of output cell carcinogenesis, wherein analytic target cell refers to and in epithelial tissue, is positioned at basilar memebrane one side but not at least a portion of the cell on top layer.
15. canceration information provider units according to claim 14, is characterized in that:
This device also has for measuring the flow through mensuration sample of this flow chamber the optical information of obtaining the optical information of measuring cell contained in sample of flow chamber that sample stream crosses and irradiation and obtains parts; Wherein data acquisition section is obtained the first data and the second data according to optical information.
16. canceration information provider units according to claim 15, is characterized in that:
This device also has the shooting parts to contained cell is taken in the mensuration sample of the flow chamber of flowing through; The first data are to take the nuclear area that parts photograph, and the second data are to take the cytoplasmic area that parts photograph.
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| CN201510729551.6A CN105242034B (en) | 2011-07-22 | 2012-07-04 | Cancerous information providing method and cancerous information provide device |
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| JP2011160746A JP5138801B2 (en) | 2011-07-22 | 2011-07-22 | Canceration information providing method and apparatus |
| JP2011-160746 | 2011-07-22 | ||
| PCT/JP2012/067128 WO2013015089A1 (en) | 2011-07-22 | 2012-07-04 | Method for providing oncogenesis information and device for providing oncogenesis information |
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| ES2617229T3 (en) | 2017-06-15 |
| CN105242034B (en) | 2019-02-05 |
| US10208352B2 (en) | 2019-02-19 |
| CN103703367B (en) | 2015-12-02 |
| EP2735872A4 (en) | 2015-03-18 |
| CN105242034A (en) | 2016-01-13 |
| WO2013015089A1 (en) | 2013-01-31 |
| EP2735872A1 (en) | 2014-05-28 |
| US20140199702A1 (en) | 2014-07-17 |
| JP2013024768A (en) | 2013-02-04 |
| EP2735872B1 (en) | 2016-11-23 |
| JP5138801B2 (en) | 2013-02-06 |
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